Key Points

In patients with melanoma, the chance of disease progression after anti–PD-1 treatment decreased by 13% with each decade of life.

In animal models, pretreating with anti-CD25 decreased the number of Tregs in the tumors in young mice and increased their response to anti–PD-1 therapy.

These data show that older patients fare better on anti–PD-1 and suggest that treating refractory patients with antibodies that deplete Tregs may increase their chances of response to anti–PD-1.

Recent research has shown that the tumor microenvironment in older patients promoted melanoma metastasis and resistance to targeted therapy with a BRAF inhibitor. Now, a new study investigating the relationships among age, response to anti–programmed cell death protein 1 (PD-1) therapy, and prior treatment in patients with melanoma has found that the chance of disease progression after anti–PD-1 treatment decreased by 13% with each decade of life. In animal models, pretreating with anti–CD25 antibody decreased the number of regulatory T cells (Tregs) in the tumors in young mice and increased their response to anti–PD-1 treatment. These findings suggest the importance of age as a major factor in understanding tumor response and resistance to therapy. The study by Kugel et al is published in Clinical Cancer Research.

Study Details

In a multinational study, the researchers analyzed data from 538 patients with melanoma treated with the anti–PD-1 therapy pembrolizumab (Keytruda). A total of 238 patients were younger than 62 years, and 300 patients were aged 62 or older. They then used mouse models of melanoma to analyze the intratumoral immune microenvironment in young vs aged mice and confirmed their findings in human melanoma biopsies.

The researchers found that patients over 60 responded more efficiently to anti–PD-1 therapy, and the likelihood of response to anti–PD-1 increased with age, even when they controlled for prior MAPKi therapy. The researchers also found that placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti–PD-1 compared with the same tumors in young mice (8 weeks).

The data suggest this increased response in aging patients occurs even in the absence of a more complex mutational landscape. The researchers also found that young mice had a significantly higher population of Tregs, skewing the CD8-positive:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 antibody increased the response to anti–PD-1 in young mice.

Practical Implications

“Interestingly, younger patients who had prior MAPKi therapy had a much lower rate of complete response to anti–PD-1 than older patients who had prior MAPKi therapy (4% vs 15%),” said Ashani T. Weeraratna, PhD, Ira Brind Professor and Co-Program Leader of the Immunology, Microenvironment, and Metastasis Program at The Wistar Institute and the corresponding author of this study, in a statement. “Our results suggest that preconditioning the tumor microenvironment in younger patients by depleting Tregs could make them respond to anti–PD-1 immunotherapies better. Our studies suggest that in designing therapies for melanoma, age should be considered as a factor in both preclinical and clinical models.”

Funding for the study was provided by the National Institutes of Health, a Cancer Institute NSW fellowship (Australia), a Melanoma Research Alliance/L’Oréal Paris-USA Women in Science Team Cancer Development Award, the Melanoma Research Foundation, an ASCO/CCF Career Development Award, and a Melanoma Research Alliance Young Investigator grant.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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